Testosterone replacement therapy (TRT)is associated with a lower risk of adverse cardiovascular (CV) events among men with testosterone deficiency, according to a new study.

Researchers led by T. Craig Cheetham, PharmD, MS, of the Southern California Permanente Medical Group, identified a retrospective cohort of 44,335 men aged 40 years and older with evidence of testosterone deficiency. The cohort included 8808 men who had ever been dispensed testosterone (ever-TRT group) and 35,527 men never dispensed testosterone (never-TRT group). The primary outcome was a composite of cardiovascular endpoints that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD).

After a median follow-up of 3.2 years in the never-TRT group and 4.2 years in the ever-TRT group, the rates of the composite endpoint were significantly higher in the never-TRT than ever-TRT group (23.9 vs 16.9 per 1000 person-years), Dr Cheetham and colleagues reported online ahead of print in JAMA Internal Medicine. After adjusting for potential confounders, the ever-TRT group had a significant 33% lower risk of the primary outcome compared with the never-TRT group. The investigators found similar results when looking separately at combined cardiac events (AMI, SCD, unstable angina, coronary revascularization) and combined stroke events (stroke and TIA). The ever-TRT group had a significant 34% and 28% lower risk of cardiac events and stroke events compared with the never-TRT group, respectively.

“While these findings differ from those of recently published observational studies of TRT, they are consistent with other evidence of CV risk and the benefits of TRT in androgen-deficient men,” the investigators wrote.

Previous studies have found an association between low serum testosterone levels in aging men and an increased risk of coronary artery disease as well as an inverse relationship between serum testosterone and carotid intima thickness, Dr Cheetham’s team pointed out.

The never-TRT and ever TRT groups had a mean age of 59.8 and 58.4 years, respectively. In the never-TRT group, 13,824 men (38.9%) were aged 40 to 55 years, 10,902 (30.7%) were aged 56 to 65 years, and 10,801 (30.4%) were older than 65 years. In the ever-TRT group, 3746 men (42.5%) were aged 40 to 55, 2899 (32.9%) were aged 56 to 65 years, and 2163 (24.6%) were older than 65 years. The groups were similar with respect to race and ethnicity composition.

With regard to study limitations, the investigators noted that their criterion for identifying men with testosterone deficiency (a diagnosis or at least 1 morning testosterone measurement) does not meet the strict criteria established by the Endocrine Society. “Therefore some individuals in the study could be misclassified as being androgen-deficient.” In addition, as the study was observational in design, “unmeasured confounding may have had an influence on the results; unmeasured confounders could possibly influence clinicians to selectively use testosterone in healthier patients.”

In an accompanying editorial, Eric Orwoll, MD, of Oregon Health & Sciences University in Portland, commented that while the study by Dr Cheetham’s group “provides reassuring data concerning the effects of testosterone on cardiovascular health, convincing answers about this question—and other safety issues like prostate health—remain elusive and will require large, prospective randomized trials.

“At this point, clinicians and their patients should remain aware that the cardiovascular risks and benefits of testosterone replacement in older hypogonadal men have not been adequately resolved.”